1. Field of the Invention
The present invention relates to pharmaceutical compounds which are useful for the prevention and/or treatment of neurodegenerative diseases or the treatment of cognitive function impairment. In particular, the present invention concerns pro-drugs of 1-(2-halo-biphenyl-4-yl)alkanecarboxylic acids. The present invention also relates to methods for the prevention and/or treatment of neurodegenerative diseases or the treatment of cognitive function impairment by administering such a compound.
2. Discussion of the Background
Neurodegenerative disorders such as Alzheimer's disease are characterized from a histopathologic point of view by a diffuse presence of extracellular and perivascular neuritic plaques and intracellular neurofibrillary tangles in the cerebral parenchyma of the patients. Neuritic plaques are mainly composed of aggregates of a protein with 39-43 amino acid residues known as β-amyloid (βA) and, depending on the numbers of amino acids, they are better known as Aβ39, Aβ40, Aβ42 and Aβ43.
In addition to these histopathologic lesions, there is lack of some neurotransmitters, particularly acetylcholine, serotonin, noradrenalin, dopamine, glutamate and substance P. The pharmacological approaches aimed at increasing acetylcholine cerebral levels, mainly through the administration of acetylcholine-esterase inhibitors, attained poor results from the clinical standpoint, or anyhow results which cannot significantly prevent the progress of the disease. For this reason, in recent years interest has been focused on the mechanisms of formation of the main pathologic lesions in the brain of the patients, namely both neuritic plaques and neurofibrillary tangles, and more effective therapeutic approaches have been looked for.
In this respect, compounds have been reported which can reduce the production of the most neurotoxic isoform of β-amyloid, namely the form containing 42 amino acids (Aβ42), through their interaction with a macromolecular/multiprotein enzymatic complex with aspartyl-protease activity, known as γ-secretase.
For instance, WO 2004/074232 discloses derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid capable of modulating γ-secretase activity without affecting other important metabolic processes such as cyclooxygenase-enzymes activity. In particular, the compound 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, belonging to this class, also quoted in the literature with the experimental code CHF 5074, has been found particularly useful for treating Alzheimer disease as well as for preventing cognitive disorders.
On the other hand, drugs aimed at the treatment of C.N.S. diseases such as Alzheimer's disease, in order to efficaciously exercise their therapeutic activity, need to cross the blood-brain barrier. The passage and the distribution in the C.N.S. of polar drugs such as the carboxylic acids and their derivatives are strongly limited by the presence of said barrier.
In WO 2006/016219, pro-drugs of the 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acids of WO 2004/074232 have been disclosed wherein the carrier molecule is the amide of an amino acid, in particular glycinamide. However, said pro-drugs, notwithstanding that they are endowed with a good brain penetration, turned out to be rather stable and hardly release the active moiety.
Therefore, it would be highly advantageous to provide further carrier molecules to link said 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acids in such a way to obtain pro-drugs capable of releasing more efficiently the active moiety than those of the prior art. This problem is solved by the compounds of the present invention.